The peroxisome proliferator-activated receptor α regulates amino acid metabolism

The peroxisome proliferator-activated receptor a is alpha ligand-activated transcription factor that plays an important role in the regulation of lipid homeostasis. PPAR alpha mediates the effects of fibrates, which are potent hypolipidemic drugs, on gene expression. To better understand the biological effects of fibrates and PPAR alpha, we searched for genes regulated by PPAR alpha using oligonucleotide microarray and subtractive hybridization. By comparing liver RNA from wild-type and PPAR alpha null mice, it was found that PPAR alpha decreases the mRNA expression of enzymes involved in the metabolism of amino acids. Further analysis by Northern blot revealed that PPAR alpha influences the expression of several genes involved in trans- and deamination of amino acids, and urea synthesis. Direct activation of PPAR alpha using the synthetic PPAR alpha ligand WY14643 decreased mRNA levels of these genes, suggesting that PPAR alpha is directly implicated in the regulation of their expression. Consistent with these data, plasma urea concentrations are modulated by PPAR alpha in vivo. It is concluded that in addition to oxidation of fatty acids, PPAR alpha also regulates metabolism of amino acids in liver, indicating that PPAR alpha is a key controller of intermediary metabolism during fasting.